Rare disease red flags

Recognising when a patient’s presentation may have a rare or genetic cause can be challenging, especially in generalist settings where symptoms are often non-specific. Red flag tools simplify this process, helping clinicians spot possible signs of rare disease and enabling patients to gain faster access to further investigation and appropriate support.

Red flag systems are often used in medicine to screen for features that suggest serious underlying pathology. They are not diagnostic tests, but rather they help raise the clinician’s index of suspicion that further investigation is required. Red flag systems are also used in other areas of practice, such as when assessing a patient presenting with back pain.

Instead of trying to memorise the clinical features of thousands of individual rare diseases, it is possible to use a small number of red flag frameworks that capture shared patterns across many conditions.

These tools are particularly useful in busy, generalist settings such as primary or acute care, where presentations are often non-specific and consultations are time limited.

When used well, red flag tools prompt timely consideration of a rare or genetic cause, structured documentation of findings, and appropriate referral or testing. They also empower clinicians to listen for psychosocial cues that a patient’s diagnostic journey may not be progressing as expected.

Two examples of practical red flag tools are:

• the Family GENES tool: a structured framework for identifying genetic clues; and
• the Psychosocial Red Flags tool: a patient-derived framework identifying common journey-level warning signs.

Family GENES tool

The Family GENES tool is a memory aid for identifying potential genetic conditions in general clinical practice. It prompts clinicians to ask questions in two domains, as outlined below.

• Family history:
  • When taking a family history, aim to include information from at least three generations.
• GENES (with each letter representing a category of genetic ‘red flags’):
  • G: Groups of physical or developmental differences present from birth (isolated anatomic variations are common, but two or more variations are more likely to indicate the presence of an underlying genetic syndrome);
  • E: Extreme or exceptional presentation of common conditions – for example, early-onset cardiovascular disease, cancer or renal failure, recurrent miscarriage or multiple primary cancers affecting different tissues;
  • N: Neurodevelopmental delay or degeneration;
  • E: Extreme or exceptional pathology – for example, rare tumour types; and
  • S: Surprising laboratory values – that is, markedly atypical results.

These categories help clinicians recognise patterns that suggest a possible genetic cause, even when a specific diagnosis is not clear.

How was this tool developed?

The tool was originally proposed as a structured prompt to support the recognition of genetic conditions in general medicine (see the references list below).

Biopsychosocial Red Flags tool

The Biopsychosocial Red Flags tool highlights patterns in a patient’s health, care and lived experience that may indicate an undiagnosed rare condition. These clues are not about specific symptoms, but rather about how a person’s health journey unfolds – for example, with repeated referrals, long periods without a diagnosis, or symptoms that span multiple systems.

The tool identifies seven recurring red flags in patient journeys before diagnosis:

• multi-system involvement (three or more systems);
• a pattern of genetic inheritance (family members with similar symptoms);
• symptoms persisting from childhood into adulthood;
• difficulties at school (frequent absences, bullying or poor participation in physical education);
• multiple specialist referrals without resolution;
• unexplained symptoms over a long duration; and
• a history of misdiagnosis.

These features reflect shared experiences across rare conditions and highlight the lived impact of delayed recognition.

How was this tool developed?

The tool was devised using qualitative research with UK rare disease patient groups. The study analysed 81 participant responses representing 79 rare conditions. It used thematic analysis to identify common psychosocial and system-level patterns that were present before diagnosis (see the references section below).

The Family GENES tool focuses on biological and clinical indicators that may suggest a genetic cause. The Biopsychosocial Red Flags tool highlights journey-level and psychosocial patterns that can signal an undiagnosed rare condition.

The tools can be used together in the following way:

• screening for red flags when the presentation is unusual, multi-system or unexplained;
• synthesising findings from both tools and considering appropriate investigations or referrals; and
• supporting the patient by acknowledging uncertainty, signposting reliable information and co-ordinating follow-up.

This can support holistic assessment and earlier recognition of rare disease.

• Red flag systems can alert clinicians to individuals who may be living with undiagnosed rare disease.
• The Family GENES tool supports structured history taking and recognition of genetic clues.
• The Biopsychosocial Red Flags tool draws attention to journey-level warning signs of diagnostic delay.
• Red flag systems are not diagnostic tools, but they can alert you to cases that require further investigation and prevent premature case closure.

For clinicians

References:

• Al-Attar M, Butterworth S and McKay L. ‘A quantitative and qualitative analysis of patient group narratives suggests common biopsychosocial red flags of undiagnosed rare disease‘. Orphanet Journal of Rare Diseases 2024: volume 19, article number 172. DOI: 10.1186/s13023-024-03143-8
• Whelan AJ, Ball S, Best L and others. ‘Genetic red flags: Clues to thinking genetically in primary care practice‘. Primary Care: Clinics in Office Practice 2004: volume 31, issue 3, pages 497–508. DOI: 10.1016/j.pop.2004.04.010